August 30, 2012

Denisova genome at high coverage (Meyer et al. 2012)

The high coverage Denisova genome had been made available online in February, and now the paper to accompany it has appeared in Science. I do appreciate the fact that the Max Planck folks did not wait until publication to share their data; anything that can accelerate the process of scientific discovery is good in my book. I'll post any comments on this paper as an update when I read it.

UPDATE I: The most exciting thing about this paper, even above and beyond the new information it provides is the new technology of single strand sequencing. From a ScienceNOW story:

Meyer's breakthrough came in developing a method to start the sequencing process with single strands of DNA instead of double strands, as is usually done. By binding special molecules to the ends of a single strand, the ancient DNA was held in place while enzymes copied its sequence. The result was a sixfold to 22-fold increase in the amount of Denisovan DNA sequenced from a meager 10-milligram sample from the girl's finger. The team was able to cover 99.9% of the mappable nucleotide positions in the genome at least once, and more than 92% of the sites at least 20 times, which is considered a benchmark for identifying sites reliably.

...

Back in Leipzig, the mood is upbeat, as researchers pull fossil samples off the shelf to test anew with "Matthias's method." First on Paabo's list: Neandertal bone samples, to try to produce a Neandertal genome to rival that of the little Denisovan girl.

There are two reasons to be very happy:

First, the new method will probably open new vistas in ancient DNA, as it represents an order of magnitude improvement in the amount of coverage that can be accomplished.

Second, the authors were able to estimate the age of the specimen by cleverly measuring how much it differed from chimpanzees vs. how much we, living humans, so differ. As they explain in the supplement:

Based on the differences in branch length to the common ancestor of human and chimpanzee (1.13% to 1.27%; see Table S13), we estimate that the observed branch shortening corresponds to 73,614 – 82,421 (average 75,443) years assuming a human-chimpanzee divergence time of 6.5 million years.

Note that recent developments in dating human-chimpanzee divergence may push it to an older date than 6.5 million years. But, even if that date is accepted, the Denisova specimen is now the oldest Homo sequenced and our ability to get high-coverage DNA from a ~75ka specimen means that we may be getting DNA from other really old samples. Human evolutionary genetics is going to be very interesting in the coming years!

UPDATE II (East Eurasians more Neandertal than Europeans):
There were hints of this in the previous papers, but they did not reach statistical significance. Now, it appears that they are confirmed. From the paper:

Interestingly, we find that Denisovans share more alleles with the three populations from eastern Asia and South America (Dai, Han, and Karitiana) than with the two European populations (French and Sardinian) (Z=5.3). However, this does not appear to be due to Denisovan gene flow into the ancestors of present-day Asians, since the excess archaic material is more closely related to Neandertals than to Denisovans (Table S27). We estimate that the proportion of Neandertal ancestry in Europe is 24% lower than in eastern Asia and South America (95% C.I. 12-36%).

This finding is important, because it shows that the simple model of modern humans expanding Out-of-Africa, interbreeding with Near Eastern Neandertals and carrying on to the rest of the world, carrying with them a fraction of Neandertal ancestry is incomplete.

Some explanations for this finding are discussed on p. 41 of the supplement. The fact that Neandertals were a West Eurasian-distributed species is at great odds with the finding of greater Neandertal admixture in Asian/American populations. But, if the Iceman, and, by implication, Paleolithic Europeans were more similar to Neandertals still, a further complication is added. This may be consistent with ideas from palaeoanthropology about great levels of variation in late Pleistocene humans compared to recent ones. One can imagine that groups varied substantially in their proportions of Neandertal ancestry until fairly recent times, but homogenizing gene flow evened out what was initially a very uneven distribution, but not completely.

UPDATE III (Mutation rate):
The paper appears in a transitional period in our understanding of mutation rates. So, while it presents a much better Denisova genome than the earlier published one, our understanding of how and when the Denisova population diverged from modern humans is now less clear. I have covered some of the mutation rate controversies recently on the basis of three papers: Kong et al., Sun et al., and Langergraber et al.

The discussion in Supplementary Note 10 summarizes the increased uncertainty about the topic:

An important date in human evolution is when the ancestors of modern humans diverged from Denisovans and their sister group the Neandertals. In the paper on the draft sequence of the Neandertal genome, we estimated this date for Neandertals (1). Since Denisovans are a sister group of Neandertals (2), they should have approximately the same population divergence; however, we never assessed this directly. Furthermore, the inference in the Neandertal genome paper was based on assumptions about mutation rates from early 2010. Since that time, better data have become available, lower mutation rates have been suggested, and the true value of the mutation rate has become less certain. It is important to obtain a new date estimate in light of this.

Paleontological calibration can only take us so far; for example, Neandertaloid traits in the Atapuerca hominins suggest an early split with modern humans and therefore a low mutation rate, but they also suggest a much earlier human-chimp speciation time than commonly thought. I think that a technical solution to the problem will eventually be found, which will show why there is the 2-fold difference in mutation rate estimates.

UPDATE IV (Demographic History):
The plot on the left shows inferred changes in population size for 12 different populations, using the PSMC approach of Li & Durbin.

One can see that the different populations seem to match quite well until ~750/375ky (depending on mutation rate), when Denisovan population starts decreasing, and the population of the modern human groups starts increasing. Then at ~110/55ky, population sizes in modern humans begin diverging.

There are two ways to look at this: if one assumes tree-like divergence of population, then obviously the fact that Denisova spends the period between 750/375 to 100/50ky at a much lower population size than modern humans speaks of an isolated population with limited genetic diversity.

But, as I've mentioned before in this blog, genetic diversity can be created by admixture. Take two populations that diverged a long time ago, even ones with low intra-population diversity, mix them, and the end result will be one very diverse population. In the absence of admixture, variation is generated by mutation, and culled by drift and selection. But, mutation is a random process that adds variation incrementally into the population, with new alleles appearing at a rate ~ to the number of breeding bodies times the mutation rate/per genome. Admixture, on the other hand, introduces a whole bunch of new alleles in a limited amount of time.

Here is what I think may havehappened; I will use the older dates, as they currently make more sense to me:

Homo heidelbergensis emerges in western parts of the Old World c. 750ky. Whatever adaptations gave heidelbergensis a bigger brain than erectus spread quickly throughout Europe and Africa. Admixture between European and African hominins at this time and/or expansion of the H. h. population lead to an increase in population size.

Further east, heidelbergensis is less visible, and older erectus populations persist. The Denisovan population can then be seen as an eastern H. h. that had more limited opportunity to expand and/or experience gene flow, because of its remote location; the Deniosovans were not unlike isolated Siberian groups of today: substantially less diverse than the bulk of mankind.

Pre-100ka sees the rise of the modern humans. According to my "two deserts" theory, these were a population of AMH living in North Africa.

Post-100ka population histories begin to diverge, but with all population sizes decreasing (consistent with the rise of behaviorally modern humans carrying a small subset of the genetic variation in the broader group of archaic H. sapiens / anatomically modern humans). This is the major bottleneck of modern human origins that has transformed us into a fairly homogeneous species.

But, Africans and non-Africans follow different trajectories, with the former maintaining higher population sizes than the latter. This is probably related to the ecological calamities that befell Eurasians during the 100-50ka period (notably the drying up of the Sahara-Arabia belt post-70ka and /or the Toba eruption), and also to a partial breakdown of African population structure as modern humans expanded deeper into Sub-Saharan Africa and started mixing with pre-existing humans living there, consistent with signals of archaic admixture detected for this period.

Science DOI: 10.1126/science.1224344

A High-Coverage Genome Sequence from an Archaic Denisovan Individual

Matthias Meyer et al.

We present a DNA library preparation method that has allowed us to reconstruct a high-coverage (30X) genome sequence of a Denisovan, an extinct relative of Neandertals. The quality of this genome allows a direct estimation of Denisovan heterozygosity, indicating that genetic diversity in these archaic hominins was extremely low. It also allows tentative dating of the specimen on the basis of “missing evolution” in its genome, detailed measurements of Denisovan and Neandertal admixture into present-day human populations, and the generation of a near-complete catalog of genetic changes that swept to high frequency in modern humans since their divergence from Denisovans.

23 comments:

"The quality of this genome allows a direct estimation of Denisovan heterozygosity, indicating that genetic diversity in these archaic hominins was extremely low".

A low heterozygosity would indicate an inbred population. If such is the case it is unlikely that contemporary humans in SE Asia were at all closely related. It is quite a convincing argument that Papuans/Australians passed somewhere close by the Altai during their expansion to and beyond SE Asia.

The new "enhanced" D-statistic is also of interest (restricts analysis to alleles that are not present in 35 African genomes). This seems to yet again confirm that admixture is real and not due to African sub-structure - but I still wished they had also done a basic D-statistic with the intersect of Neanderthal and Denisovan SNPs. Perhaps we just have to wait until the better-quality Neanderthal genome is in.

Anyway, great and very promising technology.

BTW, from the population size figure (5b) to me, the later dates make more sense. Although I previously conjectured that Denisova may be heidelbergensis-like, Fig. 5b suggest an erectus-type population history that remained fairly constant around 1-2Mya but then started declining with the spread of the more modern African/West Eurasian lineages, including heidelbergensis. Again taking the later date, Denisova would have had a population size ~tripling during the climatic optimum ~105,000-125,000 ya, followed by immediate reduction and demise with the advent of modern humans shortly thereafter (consistent with the assumption that some spread immediately from Arabia during favorable times).

The later date is also consistent with a first expansion of European and Han lineages ~40,000ya.

terryt, the authors address this. Based on the short segment lengths within the low heterozygosity, they come to the conclusion that this is not due to inbreeding, but either a generally low population number, or one that used to be very low and just recently expanded.

Interestingly, we find that Denisovans share more alleles with the three populations from eastern Asia and South America (Dai, Han, and Karitiana) than with the two European populations (French and Sardinian) (Z = 5.3). However, this does not appear to be due to Denisovan gene flow into the ancestors of present-day Asians, since the excess archaic material is more closely related to Neandertals than to Denisovans (table S27). We estimate that the proportion of Neandertal ancestry in Europe is 24% lower than in eastern Asia and South America (95% C.I. 12–36%).

Dieneke, what do you think about John Hawks' criticism of the this paper's estimate of higher Neanderthal admixture in East Asians and Amerindians than in Europeans in his overview of the paper? There he writes:

"This is a very interesting result, partially because it is the opposite of what we are finding. As I explained earlier this year, we are finding Europeans to share more Neandertal alleles than Asians do. The difference in our results has been much smaller than 24%; really only an increase of less than 0.5% on the whole genome, or maybe 10% relative to the overall amount in Europe (which is on the order of 3%).

My initial reaction to this difference is that it reflects the sharing of Neandertal genes in Africa. Meyer and colleagues filtered out alleles found in Africa, as a way of decreasing the effect of incomplete lineage sorting compared to introgression in their comparison. But if Africans have some gene flow from Neandertals, eliminating alleles found in Africans will create a bias in the comparison. If (as we think) some African populations have Neandertal gene flow, that probably came from West Asia or southern Europe. So as long as the present European and Asian (and Native American) samples have undergone a history of genetic drift, or if (as mentioned in the quote) they mixed with slightly different Neandertal populations, this bias will tend to make Asians look more Neandertal and Europeans less so."

For Update II: John Hawks also covers this article with a detailed blog post. (Not a surprise, the topic is his main interest.) He suggests a good explanation for this data. I copy that part there, so everybody can see here without moving to the other blog. :)

"My initial reaction to this difference is that it reflects the sharing of Neandertal genes in Africa. Meyer and colleagues filtered out alleles found in Africa, as a way of decreasing the effect of incomplete lineage sorting compared to introgression in their comparison. But if Africans have some gene flow from Neandertals, eliminating alleles found in Africans will create a bias in the comparison. If (as we think) some African populations have Neandertal gene flow, that probably came from West Asia or southern Europe. So as long as the present European and Asian (and Native American) samples have undergone a history of genetic drift, or if (as mentioned in the quote) they mixed with slightly different Neandertal populations, this bias will tend to make Asians look more Neandertal and Europeans less so."

Currently, Pääbo and Matthias Meyer et al. have the very well-covered Denisovan genome, while the Neanderthal one is lacking. As such, I think Hawks has a bit of a statistical disadvantage.

As I have mentioned numerous times in this blog, the intersection of Neanderthal and Denisovan genome, and the therefrom derived statistics of both ancient and derivative alleles is going to be crucial, IMO.

This paper brings a wealth of new data. I was particularly fascinated by the results of the Dinka.

They are the closest relatives of Eurasians among the African samples. According to Table S24, the French have a D-statistic of 0.6% relative to the Dinka, and 1.0-1.2% relative to the other African samples (Mandenka, Yoruba, Mbuti, San). My initial response to this result was simple; it seems like Dinka have Neanderthal ancestry. Upon further inspection, however, things do not appear that simple.

The Nea(Europe, Africa) statistic (Table S28) was designed to find excess Neanderthal ancestry in Europeans. Here, the situation is completely reversed. The estimate of Neanderthal ancestry in Europeans is highest with the Dinka reference. So, what's different in this analysis? The Nea(H1,H2) statistic is limited to the parts of the genome where Denisovans carry the derived allele. If Dinka are more different from Denisovans at these positions than all other Africans, then this would mean that other Africans have an increased affinity with the Denisova-Neanderthal branch. Interestingly, John Hawks found a decreased Neanderthal similarity in the Luhya, in comparison to Yoruba. Autosomally, Luhya fit very well a mixture of West African (similar to Yoruba) and Nilo-Saharan (similar to Dinka), with some Pygmy thrown in.

This sounds as crazy to me as it does to you. Alternative explanations are welcome.

As for the decreased Neanderthal affinities of modern Europeans (note that Paleolithic Europeans seem to have been much more Neanderthal), that could be explained with ancient African gene flow. This is one of the possibilities discussed by the authors in the paper. It would also explain why West Eurasians are the closest Eurasian relatives of Africans.

How did a population that was present in Melanesia leave traces in Siberia without leaving any genetic legacies in between?

The Toba eruption may have opened SE Asia to modern human migrants by temporarily destroying jungles that had kept out more fit hominins while simultaneously decimating the Denisovan population in the middle of their geographic range where Toba's impact was greatest. This may also have provided a Denisovan-DNA free zone from which later Asian populations could emerge.

Denisovans may have fled incoming modern humans or been slaughtered by them in circumstances where Neanderthals would have stood their ground and admixed. Neanderthals had tools comparable in efficacy to those of the first Mesolithic modern humans they encountered and similar brain size relative to body size; Homo Erectus (from whom Denisovans are likely derived at least in part) had smaller brains than modern humans and inferior tools. Thus, Denisovans may have been far more clearly outmatched. But, exile may not have been an option in ISEA because they couldn't swim long distances or make boats. Denisovan's who had undergone island dwarfism in Flores, however, might have escaped slaughter, where their non-pygmy kin did not, because they didn't seem like as much of a threat to incoming modern humans. Archaic hominins in Flores and modern humans co-existed on that small island for 25,000 years, longer in such close proximity anywhere else in the world. So even if fertile hybrids were rare, there might still have been some in Flores.

Denisovan-modern human couplings may have been less likely to produce fertile offspring than pairing between the more closely related Neanderthals and modern humans as a result of their greater genetic distance. There could even have been just one fertile Denisovan hybrid child in all of history, perhaps in Flores where the Denisovan population was cornered, who genes were amplified by the extreme population bottle neck in the founding populations of Papua New Guinea and the Sahul which had an effective population of fewer than 100 and could have involved just 6 to 12 women. Sound improbable? What if the small extended family and a few other friends of the only fertile Denisovan-modern human hybrid child made the do or die decision to sail off into the horizon where they could see no destination that put them in Sahul (the only part of the trip to Australia and Papua New Guinea that couldn't be made by navigation to a visible destination), so that they could flee persecution because they were tied to the hybrid Denisovan child, where they were sure that no one would follow and the only reason they had to believe they would find land was faith in providence.

First wave modern humans who were admixed with Denisovans could also have been profoundly diluted by later waves of modern humans from the Denisovan "dead zone" where they were nearly wiped out by Toba. Paleolithic carriers of Y-DNA haplogroup O could have expanded into Western Indonesia when it was part of a Sundland pennisula connected to mainland Asia and mainland Asia. Later waves of Asian Neolithic migrants could have diluted them again.

How could Paleolithic hunter-gatherers with Y-DNA halogroup O so powerfully diluted prior Paleolithic hunter-gatherer populations? Perhaps their decisive advantage over first wave modern humans and (and perhaps also Y-DNA hg D rich populations), is that they had domesticated dogs, while the prior populations did not.

"Based on the short segment lengths within the low heterozygosity, they come to the conclusion that this is not due to inbreeding, but either a generally low population number, or one that used to be very low and just recently expanded".

But either of those options still imply quite a level of inbreeding. A 'generally low population number', for any length of time, necessarily indicates inbreeding. And a population 'that used to be very low and just recently expanded' also necessitates a period of inbreeding before the expansion.

"Paleolithic carriers of Y-DNA haplogroup O could have expanded into Western Indonesia when it was part of a Sundland pennisula connected to mainland Asia and mainland Asia. Later waves of Asian Neolithic migrants could have diluted them again".

I don't think the Paleolithic carriers of Y-DNA haplogroup O reached Indonesia until much later than the Upper Paleolithic. Probably only with the arrival of the Easrly neolithic.

Probably because southern China and SE Asia were but sparsely inhabited until the Neolithic expansion. That the population numbers in southern China have increased significantly only recently is indicated by the survival of the panda in the region and the reasonably recent extinction of orangutans in South China. The last survive at present only in Borneo and Sumatra, so presumably these two islands too were sparsely settled until the Neolithic expansion.

"Further east, heidelbergensis is less visible, and older erectus populations persist. The Denisovan population can then be seen as an eastern H. h. that had more limited opportunity to expand and/or experience gene flow, because of its remote location"

But you've already written:

"obviously the fact that Denisova spends the period between 750/375 to 100/50ky at a much lower population size than modern humans speaks of an isolated population with limited genetic diversity".

That rather eliminates the possibility that the Denisova and SE Asian H. erectus populations are at all closely related. Even John Hawks admits at:

I think people have seriously underestimating the difficulty of moving overland from western India to southeast Asia compared to moving from southern Siberia. There are of course the Himalayas but also the incredibly tough terrain between what is today Assam, Myanmar, and Yunnan, with 2--3,000 foot escarpments in jungles filled with big animals, snakes, malaria, etc., the river gorges virtually impossible to traverse even now. Between the Indian border today and Mandalay in Myanmar (a few hundred miles) are no less than 23 bridges over high gorges (see Where China Meets India for all the local geography and ancient history of population movements). On the other hand, Yunnan and adjacent parts of Myanmar are very much part of the steppe lands of Inner Asia. The Mongols conquered Yunnan before the China. Yunnan was arguably connected to Scythian and other Inner Asians cultures in premodern times. The point is that it was far easier for people to move from southern Siberia and Mongolia to southeast Asia than from India to southeast Asia until the advent of cross-Bay of Bengal sailing. It's no wonder that someone today from Ulaan Baator might "pass" for a native in Java, more easily than someone from Delhi. To conclude, the Denisova (as a place) to Australia journey seems much easier to me than a trip from say the Ganges basin.

Nor if the "Denisovan" admix signal in Australasians and Negritos is actually shared ancestry that doesn't include African Archaic admixture nor excess Neanderthal admixture that later migrants like E Asians do have.

I have always wondered how a small band from Siberia, who are now confirmed to have been a VERY small population, would have had such a big impact in Australasia. Even with a northern route it looks unlikely.

Well, maybe they didn't have that impact, and we are just looking at it from the wrong angle. African and West Asian pop. structure vs. Australasia and Denisova could be a better explanation.---This, I think, doesn't exclude the possibility of some Erectus admixture in East Asians and Amerinds, for which there is circumstantial physical evidence but so far no genetic proof. But this is a separate issue, of course.

Hawks' criticism is methodological. So his statistical disadvantage has little relevance.

Onur,

Yes and No. No, because in the end, it is a matter of reference population resolution.

You should read pages 36-46 of the supplement. Results are consistent with Denisovan admixture and the S-statistic.

Without a highly-resolved Denisovan genome, you don't know which is what. Here, the authors are able to conclude that what at first glance appears Denisovan really is Neanderthal (although not to the extent I wished, given the lack of reliable Neanderthal coverage).

"I think people have seriously underestimating the difficulty of moving overland from western India to southeast Asia compared to moving from southern Siberia".

Yes. People look at a map and draw a straight line, then say, 'that must have been the route'. It is a very difficult route. The Movius Line passes right between the two regions so it has always been a difficult route.

"On the other hand, Yunnan and adjacent parts of Myanmar are very much part of the steppe lands of Inner Asia".

That's an interesting perspective. I have long suspected there must be some connection but have been unable to find a reliable natural vegetation map.

"I have always wondered how a small band from Siberia, who are now confirmed to have been a VERY small population, would have had such a big impact in Australasia. Even with a northern route it looks unlikely".

I think that some pre-modern archaic H. sapiens from SE Asia has contributed to the modern Papuan/Australian population, but that is not the source of the Denisova DNA. It seems to much to believe that the same human type was found right across Siberia and down into SE Asia. I think we can assume that H. erectus was at least as varied a species as is H. sapiens. In fact likely to be more geographically varied because, presumably, less mobile.

"Well, maybe they didn't have that impact, and we are just looking at it from the wrong angle. African and West Asian pop. structure vs. Australasia and Denisova could be a better explanation".

As I've said before, that regional population structure goes back to the H. erectus/ergaster difference. Perhaps we still have remnant genes from that difference present in the modern population.

I read those pages of the supplement. There is nothing that contradicts John Hawks' statement "Meyer and colleagues filtered out alleles found in Africa, as a way of decreasing the effect of incomplete lineage sorting compared to introgression in their comparison", to the contrary, they bolster Hawks' statement. So Hawks' criticism is valid and needs to be seriously taken into account.

There is nothing that contradicts John Hawks' statement "Meyer and colleagues filtered out alleles found in Africa, as a way of decreasing the effect of incomplete lineage sorting compared to introgression in their comparison", to the contrary, they bolster Hawks' statement. So Hawks' criticism is valid and needs to be seriously taken into account.

Of course not. The main "criticism" is simply a shortcoming the author stated themselves. So, yes, the shortcoming pointed out by the authors themselves needs to be taken seriously - even if it happens to not have any consequences. ;)

"And the comparison revealed another surprise: Four percent of the Denisovan genome comes from yet another, more ancient, human—'something unknown,' Pääbo reported".

Yet another human 'species' involved in our evolution. And:

"With all the interbreeding, 'it's more a network than a tree,' points out Carles Lalueza-Fox, a paleogeneticist from the Institute of Evolutionary Biology in Barcelona, Spain".

"Now, we may be learning that the Denisovan genome itself represents different ancestral groups -- not only a more ancient "something unknown" population, but substantially the local Neandertals. That kind of mixture is not the population history described by papers on the Denisova genome so far. And a third Denisovan mtDNA from one of the third molars at the site is substantially different from the other two, pointing to greater mtDNA diversity within the Denisovan population than now known from either Neandertals or living people".

In Expanding Hybrids And The Rise Of Our Genetic Common Denominator I already raised some questions about the hybrid nature of some Denisovan chromosomes and eg. their subsequent repatterning of modern descendants in Papua New Guinea. However, I found the hybridization signal especially 'modern'. Interesting that modern admixture is still excluded by new research, implying indeed the influence of a forth, still unidentified component.

Quote:

Extensive contacts should at least have initiated a kind of fusion between the Neanderthal and Denisovan parent species into a single population where in time, due to multiple hybridization events, the variability of introgressed DNA would have been restored and integrated, into the Neanderthal genetic heritage and vice-versa. Hybrid repattering of admixed chromosomes probably wouldn't have raised Denisovan heterozygosity beyond the elevated levels observed in modern populations, and less given the outstanding native homozygosity of the sampled Denisovans as a starting point. Indeed, the Denisovan sample has a reduced heterozygosity compared to any of the present-day humans analyzed by Meyer et al, though they reported the relative ratios of heterozygosity as fairly constant, what could be considered problematic for the assumption of archaic Neanderthal admixture already present in the shared DNA with Denisovans. However, 29 coding CCDS genes could be identified with more than one fixed non-synonymous SNC where 'Denisova' carries the ancestral allele, while in eight of these (OR2H1, MUC17, TNFRSF10D, MUC6, MUC5B, OR4A16, OR9G1, ERCC5), the Denisovan individual appeared heterozygous for all SNCs present in the gene. In table S44 it can be verified that 37% of this heterozygosity can be found in chromosome 11, 13% in chromosomes 6 and 7, and 11% in chromosome 8, while eleven chromosomes are homozygous for all investigated genes. Though Meyer's team proposes this to be the result of duplications or repetitive regions, this heteromorph signature basically leaves the possibility of hybridization more than open. Since this results focus on the fixed non-synonymous SNC where Denisova carries the ancestral allele and modern humans the derived allele, the documented non-ancestral polymorphisms of Denisova even resemble modern-like admixtures.[...]Another modern-like feature of the potential Denisovan-Neanderthal hybridization is the above mentioned outstanding heterozygosity of chromosome 11, that almost screams for continuity with the hybrid signature of the same chromosome in Papuans, where Denisovan ancestry is strikingly low.

"Apparently, there was a host of archaic hominines out there, previously considered the evolutionary ‘dead ends’ from all over the world, whose traces can still be perceived as superimposed variability in the modern human genome. That is, up to now investigation on archaic admixture is mainly focused on the differences between modern populations, that increasingly emerge as the relicts of intense ‘archaic’ hybridization processes".

I agree 100%. I especially note you map of ancient hybrid flows. After all we know both M and N mt-DNAs developed a long 'stem' before expanding. Surely they had spent some time breeding with the locals they had come in touch with before they began their expansion around the world.

"But even a much lesser extend of any gradual continuation with respect to Denisova-related selective processes against hybrid incompatibility alleles would only make sense if modern populations are themselves the continuation of these same ancient hybridization processes. Apart from what this might imply for the very nature of the modern genome in general, we could at least incorporate this signature of a continuous hybridization process, that tentatively links the Altai Mountains with Oceania, in what we know about the current distribution of Denisovan admixtures. A northern route around the SE Asiatic habitat of probably very different archaic hominine populations, some of them possibly more erectus-like or even more habilis-like, such as Homo floresiensis (Argue et al., 2012), seems at present more likely than a straightforward direct southern route"

I have spent a great deal of my time on the Internet trying to convince Maju that such is the case. If you're interested my own rather long take on the process starts here:

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